1. Field of the Invention
The present invention relates to fluoro-substituted benzoylpropionic acid derivatives, to their pharmaceutically acceptable salts, to a process for their preparation and to pharmaceutical compositions comprising them.
2. Description of the Related Art
Our previous International patent application WO 95/03271 refers to 2-amino-4-phenyl-4-oxo-butyric acid derivatives of formula (IA) either as single isomers or as racemic mixture ##STR2## and pharmaceutically acceptable salts thereof, wherein
each of the groups X and Y is, independently, hydrogen, halogen, trifluoromethyl, hydroxy, C.sub.1 -C.sub.5 alkyl, benzyl, C.sub.6 -C.sub.10 aryl, OR', --SR', SOR', SO.sub.2 R' in which R' is C.sub.1 -C.sub.5 alkyl or benzyl; and
R is hydroxy, OR', amino, NHR', --N(R').sub.2, hydroxylamine or --NHOR' in which R' is as defined above;
provided that R is not hydroxy when:
(i) X and Y are simultaneously hydrogen; or PA1 (ii) X and Y are in positions 3 and 4 of the phenyl ring and are simultaneously a hydroxy group or a --OR' group in which R' is methyl; or PA1 (iii) one of the X and Y groups is hydrogen and the other is in position 4 of the phenyl ring and is hydroxy, chlorine, fluorine, methyl, n-propyl or methoxy. PA1 a) reacting a compound of formula (II) ##STR4## with a compound of formula (III) either as a single (R) or (S) enantiomer or as racemic mixture ##STR5## wherein PA1 b) converting a compound of formula (IV) either as a single (R) or (S) enantiomer or as racemic mixture into a single (R) or (S) enantiomer or racemic mixture of a compound of formula (I) wherein R is hydroxy, and, if desired, converting a compound of formula (I) wherein R is hydroxy into a compound of formula (I) wherein R is other than hydroxy.
In WO 95/03271 the compounds of formula (IA) are described as effective in inhibiting the activity of the enzymes kynureninase and/or kynurenine-3-hydroxylase which are involved in the metabolic pathway of kynurenines leading to the formation of quinolinic acid, a tryptophan neurotoxic metabolite with excitatory activity in the mammalian central nervous system. The compounds of formula (IA) may therefore be employed in the prevention and/or treatment of a variety of nervous system diseases wherein the inhibition of the enzymes kynureninase or kynurenine-3-hydroxylase is needed; namely, they can be useful in the prevention and/or treatment of a nervous system disease related to a deranged production of quinolinic acid or excessive activation of neurotransmission mediated by N-methyl-D-aspartic acid.
For example, the compounds of formula (IA) may be useful in the prevention and/or treatment of neurodegenerative pathologies including, for example, Huntington's chorea, Alzheimer's disease, Parkinson's disease, dementia caused by acquired immunodeficiency syndrome (AIDS), multi-infarctual dementia, cerebral ischemia, cerebral hypoxia and epilepsy.
The compounds of formula (IA) are, in general, soluble in aqueous vehicles suitable for parenteral administration.
In accordance with the present invention, it has now been surprisingly found that certain fluoro-substituted benzoylpropionic acid derivatives, which represent a selected class of compounds of formula (IA), not specifically disclosed in WO95/03271, possess excellent solubility. These novel fluoro derivatives, which are selective inhibitors of the enzyme Kynurenine-3-hydroxylase, are considerably more soluble than the corresponding di-chloro derivatives disclosed in WO 95/03271 and are therefore particularly useful for injectable administration purposes.